Method for producing non-hydrated fexofenadine hydrochloride and a novel crystalline form obtained thereby

ABSTRACT

The invention relates to non-hydrated fexofenadine hydrochloride which can be obtained from a fexofenadine base and hydrogen chloride, according to the reaction conditions, either in the form of a novel polymorph (“form A”), in an amorphous form, or in the form of a mixture of different polymorphs. Said novel polymorph (“form A”) can be used as a therapeutic active ingredient and can be processed to form a pharmaceutical containing the same and a pharmaceutically acceptable carrier. Said pharmaceutical is suitable for use as an antihistaminic agent, an antiallergic agent and/or a bronchodilating agent.

The present invention relates to non-hydrated fexofenadine hydrochloride.

Fexofenadine hydrochloride (4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethylphenylacetic acid hydrochloride) has formula (I) below:

and is licensed by the US Food and Drug Administration (FDA) as an antihistamine, antiallergic and bronchodilator under the trade name Allegra®.

WO-A-95/31437 describes the preparation of hydrated polymorphs, or pseudo-morphs, of fexofenadine hydrochloride (form II and form IV) and their conversion to non-hydrated polymorphous forms (form I and form III) by azeotropic distillation or water-minimizing recrystallization.

WO-A-00/71124 describes amorphous, presumably non-hydrated fexofenadine hydrochloride and its preparation, a spray drying or freeze drying being carried out as the final stage.

It has now been found that non-hydrated fexofenadine hydrochloride can be prepared from fexofenadine base and hydrogen chloride in a simple and direct manner, without the need for operations such as azeotropic distillation, water-minimizing recrystallization, spray drying or freeze drying, to give the non-hydrated fexofenadine hydrochloride in the form of a novel polymorph (“form A”) or in amorphous form or in the form of a mixture of different polymorphs, depending on the reaction conditions, wherein

-   (a) fexofenadine base is suspended in a lower alkyl nitrile, a     solution of hydrogen chloride in a lower alkanol, in a di(lower     alkyl) ether or in a lower alkyl ester of a lower alkanecarboxylic     acid is added, and the mixture is heated and then cooled, after     which the non-hydrated fexofenadine hydrochloride is isolated in the     form of the novel polymorph (“form A”), or -   (b) fexofenadine base is suspended in a lower alkane, in a di(lower     alkyl) ether or in a lower alkyl ester of a lower alkanecarboxylic     acid, a solution of hydrogen chloride in a lower alkanol, in a     di(lower alkyl) ether or in a lower alkyl ester of a lower     alkanecarboxylic acid is added, and the mixture is heated and then     cooled, after which the non-hydrated fexofenadine hydrochloride is     isolated in amorphous form, or -   (c) fexofenadine base is suspended in a lower alkyl nitrile,     hydrogen chloride gas is passed into the suspension, and the mixture     is heated and then cooled, after which the non-hydrated fexofenadine     hydrochloride is isolated in the form of a mixture of different     polymorphs.

The compounds and radicals referred to above as “lower” appropriately contain up to eight carbon atoms. It is preferable to use acetonitrile as the lower alkyl nitrile, methanol as the lower alkanol, diethyl ether or diisopropyl ether as the di(lower alkyl) ether, ethyl acetate as the lower alkyl ester of a lower alkanecarboxylic acid, and n-hexane or n-heptane as the lower alkane.

Fexofenadine base (II) is obtainable in known manner from the hydrochloride of the corresponding keto ester, namely ethyl 4-[1-oxo-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethylphenylacetate (III).

The polymorph of fexofenadine hydrochloride obtainable according to variant (a) of the method according to the invention (“form A”) has a melting range of 153 to 156° C. (DSC) and is characterized by the following XRD data (Table 1): TABLE 1 XRD data of fexofenadine hydrochloride, form A (d = lattice spacing; the relative intensities were taken from the powder diagram obtained using CuK radiation.) rel. intensity d/Å (I/I_(max))/% 11.8 55 11.2 30 7.5 50 6.6 30 5.9 20 5.6 70 5.4 20 4.9 65 4.7 100 4.6 35 4.4 40 4.3 100 4.1 40 4.0 30 3.4 40

This polymorph is novel and also forms a subject of the present invention. It can be used as a therapeutic active ingredient and processed to a drug containing the active ingredient and a pharmaceutically acceptable excipient. This drug is suitable as an antihistamine, antiallergic and/or bronchodilator.

Pharmaceutically acceptable excipients which can be used in the preparation of drugs are generally known and familiar to all those skilled in the art.

By virtue of their different bioavailabilities, rates of release and solubilities, different forms of a pharmaceutical active ingredient, such as novel polymorphs in particular, can be of great benefit to the patients in question since they may allow a lowering of the dosage and/or a lengthening of the dosage intervals, making it possible to reduce the costs of the medication.

The Examples which follow will illustrate the invention without in any way limiting its scope.

EXAMPLES

The XRD spectra were recorded on a Philips ADP1700 computer-controlled powder diffractometer system with automatic divergence slit and secondary monochromator (graphite). The CuK_(α) radiation (λ (CuK_(α1))=0.15406 nm and λ (CuK_(α2))=0.15444 nm) from a copper tube (40 kV, 30 mA) was used and the spectra were recorded with Δ(2ΘN)=0.02 for a counting time of 3 s in the range 1.5°≦2Θ≦40°.

The differential scanning calorimetry (DSC) measurements were made on a METTLER DSC 821^(e) apparatus with a start temperature of 25° C., an end temperature of 250° C. and a heating rate of 10 K min⁻¹. Standard aluminium crucibles with perforated lids were used as the sample vessels. The amount of sample was about 5 mg in each case.

Example 1 Synthesis of Fexofenadine Base

30 g of piperidine derivative III, 1.7 g of sodium borohydride and 7.4 g of sodium hydroxide were suspended in 200 g of ethanol and 44 g of water, refluxed for 3-5 h and then quenched with 10 g of acetone. The solvents were stripped off under vacuum and the residue was taken up in 200 g of water/acetone (2:1). The pH was adjusted to 5.8 to 6.0 by the addition of acetic acid, causing the fexofenadine base to crystallize out. The precipitate was filtered off, washed with water and dried under vacuum at 60° C. to give 22 g (83%) of product.

Example 2 Synthesis of Fexofenadine Hydrochloride, Form A

86 g of fexofenadine base were suspended in acetonitrile (700 g), and 30 g of a 20.6 percent solution of hydrogen chloride in diisopropyl ether were added at −10 to −12° C. The reaction mixture was heated at the reflux temperature for 1 h and then cooled. The hydrochloride was isolated by filtration, washed with acetonitrile and dried under vacuum at 100° C. to give 83 g (90%) of fexofenadine hydrochloride, form A.

Example 3 Synthesis of Fexofenadine Hydrochloride, Form A

10.0 g of fexofenadine base were suspended in acetonitrile (76 g), and 1.9 g of a 38.6 percent solution of hydrogen chloride in methanol were added at −10 to −12° C. The reaction mixture was heated at the reflux temperature for 1 h and then cooled. The hydrochloride was isolated by filtration, washed with acetonitrile and dried under vacuum at 100° C. to give 10.1 g (94%) of fexofenadine hydrochloride, form A.

Example 4 Synthesis of fexofenadine Hydrochloride, Form A

10.0 g of fexofenadine base were suspended in acetonitrile (76 g), and 3.7 g of a 19.5 percent solution of hydrogen chloride in ethyl acetate were added at −10 to −12° C. The reaction mixture was heated at the reflux temperature for 1 h and then cooled. The hydrochloride was isolated by filtration, washed with acetonitrile and dried under vacuum at 100° C. to give 9.8 g (91%) of fexofenadine hydrochloride, form A.

Example 5 Synthesis of Amorphous Fexofenadine Hydrochloride

10.0 g of fexofenadine base were suspended in n-heptane (90 g), and 4.02 g of a 17.9 percent solution of hydrogen chloride in diisopropyl ether were added at −10 to −12° C. The reaction mixture was heated at the reflux temperature for 1 h and then cooled. The hydrochloride was isolated by filtration, washed with n-heptane and dried under vacuum at 100° C. to give 9.7 g (90%) of amorphous fexofenadine hydrochloride.

Example 6 Synthesis of Amorphous Fexofenadine Hydrochloride

10.0 g of fexofenadine base were suspended in tert-butyl methyl ether (90 g), and 4.0 g of a 17.9 percent solution of hydrogen chloride in diisopropyl ether were added at −10 to −12° C. The reaction mixture was heated at the reflux temperature for 1 h and then cooled. The hydrochloride was isolated by filtration, washed with tert-butyl methyl ether and dried under vacuum at 100° C. to give 10.5 g (98%) of amorphous fexofenadine hydrochloride.

Example 7 Synthesis of Fexofenadine Hydrochloride in the Form of a Mixture of Different Polymorphs

5.1 g of fexofenadine base were suspended in acetonitrile (39 g). 0.4 g of hydrogen chloride was passed into the suspension at −10 to −12° C., after which the mixture was heated at the reflux temperature for 1.5 h and then cooled. The hydrochloride was isolated by filtration, washed with acetonitrile and dried under vacuum at 00° C. to give 5.1 g (92%) of fexofenadine hydrochloride in the form of a mixture of different polymorphs. 

1-6. (canceled)
 7. A method of making a non-hydrated fexofenadine hydrochloride in the form of a novel polymorph (“form A”) comprising the steps of: (a) suspending a fexofenadine base in a lower alkyl nitrile to form a suspension, (b) adding a solution of hydrogen chloride in one of a lower alkanol, a di(lower alkyl) ether or a lower alkyl ester of a lower alkanecarboxylic acid to the suspension of step (a) to form a mixture; (c) heating the mixture from step (b) to form a heated mixture; (d) cooling the heated mixture from step (c) to form a cooled mixture; and (e) isolating the non-hydrated fexofenadine hydrochloride in the form of the novel polymorph (“form A”) from the cooled mixture of step (d).
 8. The method of claim 7, wherein the lower alkyl nitrile is acetonitrile.
 9. The method of claim 7, wherein the lower alkanol is methanol.
 10. The method of claim 7, wherein the di(lower alkyl) ether is diethyl ether or diisopropyl ether.
 11. The method of claim 7, wherein the lower alkyl ester of a lower alkanecarboxylic acid is ethyl acetate.
 12. A non-hydrated fexofenadine hydrochloride in the form of a novel polymorph (“form A”), obtainable according to the method of claim 7, wherein the novel polymorph has the following XRD data: rel. intensity D/Å (I/I_(max))/% 11.8 55 11.2 30 7.5 50 6.6 30 5.9 20 5.6 70 5.4 20 4.9 65 4.7 100 4.6 35 4.4 40 4.3 100 4.1 40 4.0 30 3.4 40


13. A drug composition comprising: a polymorph non-hydrated fexofenadine hydrochloride (“form A”) according to claim 7; and a pharmaceutically acceptable excipient.
 14. A method of using a non-hydrated fexofenadine hydrochloride in the form of a novel polymorph (“form A”), comprising administering the novel polymorph to a patient in need thereof.
 15. A method of making a non-hydrated fexofenadine hydrochloride in an amorphous form comprising the steps of: (a) suspending a fexofenadine base in a lower alkane, a di(lower alkyl) ether or a lower alkyl ester of a lower alkanecarboxylic acid to form a suspension; (b) adding to the suspension from step (a) a solution of hydrogen chloride in one of a lower alkanol, a di(lower alkyl) ether or a lower alkyl ester of a lower alkanecarboxylic acid to form a mixture; (c) heating the mixture from step (b) to form a heated mixture; (d) cooling the heated mixture from step (c) to form a cooled mixture; and (e) isolating the amorphous form of the non-hydrated fexofenadine hydrochloride from the cooled mixture of step (d).
 16. The method of claim 15, wherein the lower alkane is n-hexane or n-heptane.
 17. The method of claim 15, wherein the di(lower alkyl) ether is diethyl ether or diisopropyl ether.
 18. The method of claim 15, wherein the lower alkyl ester of a lower alkanecarboxylic acid is ethyl acetate.
 19. The method of claim 15 wherein the lower alkanol is methanol.
 20. A method of making a non-hydrated fexofenadine hydrochloride in a mixture of different polymorphs comprising the steps of: (a) suspending a fexofenadine base in a lower alkyl nitrile to form a suspension; (b) passing a hydrogen chloride gas into the suspension to form a mixture; (c) heating the mixture from step (b) to form a heated mixture; (d) cooling the heated mixture from step (c) to form a cooled mixture; and (e) isolating the mixture of different polymorphs from the cooled mixture of step (d).
 21. The method of claim 20 wherein the lower alkyl nitrile is acetonitrile. 